Dendritic cells are critical cells in innate immunity because of their specialized capacities to capture antigens, process them for presentation to T cells, and then initiate specific cell mediated protection and memory. It has become apparent that dendritic cells have many cell surface receptors that increase the efficiency of antigen capture by at least 100 fold. We have developed a new approach to harness these receptors in intact animals, and then improve the capacity of dendritic cells to induce protection against clinically important proteins. These protein antigens are engineered into the heavy chain of monoclonal antibodies that selectively bind to receptors involved in antigen uptake. Utilizing DEC-205/CD205 as the first target receptor, we have shown that the antibody delivers antigens to dendritic cells throughout the lymphoid system. We will use this approach to identify tumor antigens that will be able to overcome self-tolerance and elicit protective anti-tumor immunity. We will likewise extend preliminary data and show how antigens from the parasite Leishmania major can polarize the CD4+ helper cells of disease susceptible BALB mice to a protective Th1 type. Then we will address the function of other antigen presenting cells in mice by targeting antigens within monoclonal antibodies. These antibodies will target 3 different receptors on macrophages and their subsets, to selectively dissect the function of macrophages in antigen presentation to B cells and T cells in intact lymphoid organs. Likewise, we will analyze the function of additional receptors on dendritic cells, including those that are expressed on subsets of these critical antigen presenting cells. This new approach developed in the current funding period will allow investigators to study the function of dendritic cells in intact animals without having to isolate and perturb these cells in culture. Importantly, the research bears upon several issues in public health, because the aims set the stage to develop vaccines that are based on simple safe proteins and will resist both tumors and infectious diseases. By directly targeting vaccines to specific receptors on different types of antigen presenting cells, particularly dendritic cells and their subsets, we will learn to harness their critical functions for immunization and vaccination in an intact host.